Process for preparing nematicidal benzoxazole and benzthiazole compounds

ABSTRACT

A process for preparing a compound of formula (I) ##STR1## wherein X is oxygen or sulphur, by (a) reacting a substituted ortho-nitro or -nitroso phenol or a substituted ortho-nitro or -nitroso thiophenol with an alkali metal dithionite reducing agent in an alkaline reaction medium in the presence of carbon disulphide, to form a substituted 2-mercaptobenz-oxazole or -thiazole, acidifying the reaction mixture and collecting the 2-mercaptobenz-oxazole or -thiazole; and then (b) reacting the 2-mercaptobenz-oxazole or -thiazole with a compound of formula (IV) 
     
         CF.sub.2 ═CH--CH.sub.2 --CH.sub.2 --L                  (IV) 
    
     wherein L is a good leaving group.

This invention relates to a chemical process for the preparation of compounds useful as nematicides, and to intermediates of use in the process.

In United Kingdom Patent Publication No. 2270689 we have disclosed a series of nematicidal 2-(4,4-difluoro-but-3-enylthio)-benzoxazoles and benzthiazoles, and methods of preparing them. The present application relates to an improved method for preparing nematicidal 2-(4,4-difluoro-but-3-enylthio)-benzoxazoles and benzthiazoles.

According to the present invention there is provided a process for the preparation of a compound of formula (I)

wherein R¹, R², R³, and R⁴ are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted arylalkoxy, alkoxy, alkenyloxy, alkynyloxy, hydroxyalkyl, alkoxyalkyl, alkylthio, alkenylthio, alkynylthio, haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, haloalkenyloxy, haloalkynyloxy, haloalkylthio, haloalkenylthio, haloalkynylthio, halogen, hydroxy, cyano, nitro, --NR⁵ R⁶, --NR⁷ COR⁸, --NR⁷ CSR⁸, --NR⁹ SO₂ R¹⁰, --N(SO₂ --R¹¹), --(SO₂ --R¹²), --COR¹³, --CONR¹⁴ R¹⁵, --COOR¹⁶, --OCOR¹⁷, --OSO₂ R¹⁸, --SO₂ NR¹⁹ R²⁰, --SO₂ R²¹, --SOR²², --CSNR²³ R²⁴, --SiR²⁵ R²⁶ R²⁷, --OCH₂ CO₂ R²⁸, --OCH₂ CH₂ CO₂ R²⁹, --SO₂ Z, --CONR³⁰ SO₂ R³¹, --NHCONR³² R³³, --NHCSNR³² R³³ or an adjacent pair of R¹, R², R³ and R⁴ when taken together form a fused 5- or 6-membered carbocyclic or heterocyclic ring; R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³² and R³³ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl and optionally substituted arylalkyl; Z is halogen;

and X is oxygen or sulphur,

which comprises (a) reacting a substituted ortho-nitro or -nitroso phenol or a substituted ortho-nitro or -nitroso thiophenol of formula (II), wherein R¹ -R⁴ and X have the values previously defined, and y is 1 or 2, with a reducing agent comprising an alkali metal dithionite in an alkaline reaction medium in the presence of carbon disulphide, to form the substituted 2-mercaptobenz-oxazole or -thiazole of formula (III) wherein R¹ -R⁴ and X have the values previously defined, acidifying the reaction mixture and collecting the 2-mercaptobenz-oxazole or -thiazole; and

(b) reacting the 2-mercaptobenz-oxazole or -thiazole (III), with a compound of formula (IV) wherein L is a good leaving group to form the compound of formula (I).

Preferably the reducing agent is sodium, potassium or caesium dithionite. Sodium diothionite is especially preferred.

The alkaline reaction medium is preferably an aqueous alcoholic solution of an alkali metal hydroxide, for example a solution of sodium or potassium hydroxide in methanol or ethanol containing water (e.g. methanol or ethanol containing about 5 to about 15% by volume of water). The reaction temperature at atmospheric pressure is preferably from room temperature up to about 80° C.

The reaction of the 2-mercaptobenz-oxazole or -thiazole (III) with the compound of formula (IV) is carried out under conditions well known in the art for such displacement reactions, for example in the presence of a mild base such as an alkali metal carbonate, for example potassium or sodium carbonate, in an inert solvent, at a temperature in the range from about 40° C. to about 100° C. at atmospheric pressure, and conveniently at the reflux temperature of a suitable inert solvent such as acetone, which has a boiling point within this range.

The group L in compound (IV) may be for example an OSO₂ R^(a) group wherein R^(a) is a C₁₋₄ alkyl group, or a phenyl group optionally substituted with a C₁₋₄ alkyl group, for example para-tolyl, or it may preferably be a halogen atom, such as chlorine, bromine and iodine. Bromine is especially preferred.

When any one of R¹ to R⁴ is a substituted alkyl group, the substituent or substituents may comprise nitro; cyano; alkoxyimino, wherein the alkoxy group preferably has 1 to 6 carbon atoms; alkoxycarbonyl of 2 to 4 carbon atoms; carbamoyl; mono- or di-alkylcarbamoyl wherein the one or two alkyl groups preferably each have from 1 to 6 carbon atoms; amino; mono- or di-alkylamino wherein the one or two alkyl groups each preferably have from 1 to 6 carbon atoms; acylamido wherein the acyl group is formyl or an alkylcarbonyl group of 2 to 6 carbon atoms; alkanesulphonyl preferably of 1 to 6 carbon atoms; or arylsulphonyl, for example benzenesulphonyl, optionally substitued by halogen, C₁₋₄ alkoxy or nitro.

When any one of R¹ to R⁴ is a substituted alkenyl group, the substituent or substituents may comprise for example nitro or cyano.

When any one of R¹ to R³³ is an alkyl group it may be straight or branched chain and is preferably C₁₋₆ alkyl, and in particular C₁₋₄ alkyl, for example methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl.

When any one of R¹ to R³³ is an alkenyl or alkynyl group it may be straight or branched chain and is preferably C₂₋₆ alkenyl or C₂₋₆ alkynyl, for example vinyl, allyl, but-3-enyl, 3-methyl-but-3-enyl, ethynyl or propargyl.

When any one of R¹ to R⁴ is a cycloalkyl or alkylcycloalkyl group, it is preferably C₃₋₆ cycloalkyl or C₄₋₇ alkylcycloalkyl, for example, cyclopropyl, cyclopentyl, cyclohexyl or methylcyclopropyl.

When any one of R¹ to R³³ is an optionally substituted aryl or an optionally substituted arylalkyl group, it is preferably an optionally substituted phenyl group or an optionally substituted phenyl-C₁₋₂ -alkyl group, wherein the preferred optional substitution is one or more substituents selected from halogen such as chlorine, fluorine or bromine, C₁₋₄ alkyl such as methyl or ethyl, C₁₋₄ alkoxy such as methoxy or ethoxy, C₁₋₄ haloalkyl such as chloromethyl, fluoromethyl, trifluoromethyl or 2,2,2-trifluoroethyl, C₁₋₄ haloalkoxy such as trifluoromethoxy or 2,2,2-trifluoroethoxy, hydroxy, cyano and nitro, for example phenyl, benzyl, 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-nitrobenzyl or 4-methylbenzyl.

When any one of R¹ to R⁴ is an optionally substituted aryloxy or an optionally substituted arylalkoxy group, it is preferably optionally substituted phenoxy or optionally substituted phenyl-C₁₋₂ -alkoxy, group, wherein the preferred optional substitution is one or more substituents selected from halogen such as chlorine, fluorine or bromine, C₁₋₄ alkyl such as methyl or ethyl, C₁₋₄ alkoxy such as methoxy or ethoxy, C₁₋₄ haloalkyl such as chloromethyl, fluoromethyl, trifluoromethyl or 2,2,2-trifluoroethyl, C₁₋₄ haloalkoxy such as trifluoromethoxy or 2,2,2-trifluoroethoxy, hydroxy, cyano and nitro, for example phenoxy, benzoxy, 4-methylphenoxy, 4-chlorophenoxy, 4-fluorophenoxy, 4-nitrophenoxy, 3-trifluoromethylphenoxy, 4-trifluoromethylphenoxy 4-chlorobenzoxy, 4-fluorobenzoxy, 3-trifluoromethylbenzoxy, 4-trifluoromethylbenzoxy, 4-nitrobenzoxy or 4-methylbenzoxy.

When any one of R¹ to R³³ is a haloalkyl, haloalkenyl or haloalkynyl group, it may contain one or more halogen atoms selected from chlorine, fluorine or bromine, and the alkyl, alkenyl or alkynyl moiety may be straight or branched chain and is preferably C₁₋₆ alkyl, especially C₁₋₄ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2-difluoroethenyl, 3,3-dichloroprop-2-enyl, 2-chloroprop-2-enyl, 3,4,4-trifluorobut-3-enyl, 4-fluorobut-3-enyl, 4,4-difluorobut-3-enyl or 3-methyl-4,4-difluorobut-3-enyl.

When any one of R¹ to R⁴ is an alkoxy, alkenyloxy, alkynyloxy or alkoxyalkyl group, it may be straight or branched chain and is preferably C₁₋₆ alkoxy, for example methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy or t-butoxy, C₂₋₆ alkenyloxy, for example vinyloxy, allyloxy, but-3-enyloxy or 3-methylbut-3-enyloxy, C₂₋₆ alkynyloxy, for example propargyloxy, C₂₋₆ alkoxyalkyl, for example methoxymethyl, methoxyethyl or ethoxymethyl, or C₃₋₆ dialkoxyalkyl, for example dimethoxymethyl or diethoxymethyl.

When any one of R¹ to R⁴ is a haloalkoxy group, a haloalkenyloxy group or a haloalkynyloxy group, it may contain one or more halogen atoms selected from chlorine, fluorine or bromine, and the alkoxy, alkenyloxy or alkynyloxy moiety may be straight or branched chain and is preferably C₁₋₆ alkoxy, C₂₋₆ alkenyloxy or C₂₋₆ alkynyloxy, for example, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2-difluoroethenyloxy, 3,4,4-trifluorobut-3-enyloxy, 4-fluorobut-3-enyloxy, 4,4-difluorobut-3-enyloxy, 3-methyl-4,4-difluorobut-3-enyloxy, 2-chloroprop-2-enyloxy or 3,3-dichloroprop-2-enyloxy.

When any one of R¹ to R⁴ is an alkylthio group, an alkenylthio group or an alkynylthio group, the alkyl, alkenyl or alkynyl moiety is preferably C₁₋₆ alkyl, especially C₁₋₄ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, for example methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, t-butylthio, allylthio, but-3-enylthio, 3-methylbut-3-enylthio or propargylthio.

When any one of R¹ to R⁴ is a haloalkylthio group, a haloalkenylthio group or a haloalkynylthio group, it may contain one or more halogen atoms selected from chlorine, fluorine or bromine, and the alkyl, alkenyl or alkynyl moiety is preferably C₁₋₆ alkyl, especially C₁₋₄ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, for example fluoromethylthio, difluoromethylthio, trifluoromethylthio, trichloromethylthio, 2-fluoroethylthio, 2,2,2-trifluoroethylthio, 3-fluoro-n-propylthio, pentafluoroethylthio, 2-chloroprop-2-enylthio, 3,3-dichloroprop-2-enylthio, 3,4,4-trifluorobut-3-enylthio, 4-fluorobut-3-enylthio, 4,4-difluorobut-3-enylthio or 3-methyl-4,4-difluorobut-3-enylthio.

When any one of R¹ to R⁴ is halogen, it is preferably fluorine, chlorine, bromine or iodine.

When any one of R¹ to R⁴ is the group --NR₅ R₆, it is preferably --NH₂, a C₁₋₆ alkylamino group, for example methylamino or ethylamino, or a di-(C₁₋₆ alkyl)-amino group, for example dimethylamino or diethylamino.

When any one of R¹ to R⁴ is the group --NR⁷ COR⁸ it is preferably, --NHCHO, a C₂₋₆ acylamino group or an optionally substituted benzamido group, for example --NHCOCH₃, --NHCOC₂ H₅, benzamido or benzamido optionally substituted with one or more substituents selected from halogen such as chlorine, fluorine or bromine, C₁₋₄ alkyl such as methyl or ethyl, C₁₋₄ alkoxy such as methoxy or ethoxy, C₁₋₄ haloalkyl such as chloromethyl, fluoromethyl, trifluoromethyl or 2,2,2-trifluoroethyl, C₁₋₄ haloalkoxy such as trifluoromethoxy or 2,2,2-trifluoroethoxy, hydroxy, cyano and nitro.

When any one of R¹ to R⁴ is the group --NR⁷ CSR⁸, R⁷ and R⁸ are preferably each independently a C₁₋₆ alkyl group.

When any one of R¹ to R⁴ is the group --NR⁹ SO₂ R¹⁰ it is preferably a C₁₋₆ alkanesulphonamido group, for example --NHSO₂ CH₃ or --NHSO₂ C₂ H₅.

When any one of R¹ to R⁴ is the group --N(SO₂ R¹¹)(SO₂ R¹²) it is preferably a di-(C₁₋₆ alkanesulphonyl)amino group, for example --N(SO₂ CH₃)₂ or --N(SO₂ C₂ H₅)₂.

When any one of R¹ to R⁴ is the group --COR¹³, it is preferably formyl, a C₂₋₆ acyl group or an optionally substituted benzoyl group, for example acetyl, propionyl, n-butanoyl, benzoyl or benzoyl optionally substituted with one or more substituents selected from halogen such as chlorine, fluorine or bromine, C₁₋₄ alkyl such as methyl or ethyl, C₁₋₄ alkoxy such as methoxy or ethoxy, C₁₋₄ haloalkyl such as chloromethyl, fluoromethyl, trifluoromethyl or 2,2,2-trifluoroethyl, C₁₋₄ haloalkoxy such as trifluoromethoxy or 2,2,2-trifluoroethoxy, hydroxy, cyano and nitro, for example 4-chlorobenzoyl, 4-fluorobenzoyl, 4-bromobenzoyl, 4-methylbenzoyl or 4-trifluoromethylbenzoyl.

When any one of R¹ to R⁴ is the group --CONR¹⁴ R¹⁵, it is preferably --CONH₂, an N--(C₁₋₆ alkyl)-carboxamido group, for example --CONHCH₃, --CONHC₂ H₅ or --CONHCH₂ CH₂ CH₃, or an N,N-di-(C₁₋₆ alkyl)-carboxamido group, for example --CON(CH₃)₂, --CON(CH₃)(C₂ H₅) or --CON(C₂ H₅)₂.

When any one of R¹ to R³ is the group --COOR¹⁶, it is preferably --COOH, a C₁₋₆ alkoxycarbonyl group, for example methoxycarbonyl or ethoxycarbonyl, or a C₂₋₆ haloalkenyloxycarbonyl group, for example 3,4,4-trifluorobut-3-enyloxycarbonyl, 4-fluorobut-3-enyloxycarbonyl, 4,4-difluorobut-3-enyloxycarbonyl or 3-methyl-4,4-difluorobut-3-enyloxycarbonyl,

When any one of R¹ to R⁴ is the group --OCOR¹⁷, it is preferably a C₂₋₆ acyloxy group or an optionally substituted benzoyloxy, for example --OCOCH₃, --OCOC₂ H₅, benzoyloxy or benzoyloxy optionally substituted with one or more substituents selected from halogen such as chlorine, fluorine or bromine, C₁₋₄ alkyl such as methyl or ethyl, C₁₋₄ alkoxy such as methoxy or ethoxy, C₁₋₄ haloalkyl such as chloromethyl, fluoromethyl, trifluoromethyl or 2,2,2-trifluoroethyl, C₁₋₄ haloalkoxy such as trifluoromethoxy or 2,2,2-trifluoroethoxy, hydroxy, cyano and nitro.

When any one of R¹ to R⁴ is the group --OSO₂ R¹⁸, it is preferably a C₁₋₆ alkanesulphonyloxy group or an optionally substituted benzenesulphonyloxy group, for example methanesulphonyloxy, ethanesulphonyloxy, benzenesulphonyloxy or benzenesulphonyloxy optionally substituted with one or more substituents selected from halogen such as chlorine, fluorine or bromine, C₁₋₄ alkyl such as methyl or ethyl, C₁₋₄ alkoxy such as methoxy or ethoxy, C₁₋₄ haloalkyl such as chloromethyl, fluoromethyl, trifluoromethyl or 2,2,2-trifluoroethyl, C₁₋₄ haloalkoxy such as trifluoromethoxy or 2,2,2-trifluoroethoxy, hydroxy, cyano and nitro, for example 4-methylbenzenesulphonyloxy.

When any one of R¹ to R⁴ is the group --SO₂ NR¹⁹ R²⁰, it is preferably --SO₂ NH₂, a C₁₋₆ alkylaminosulphonyl group, for example --SO₂ NHCH₃ or --SO₂ NHC₂ H₅, or a di-(C₁₋₆ alkyl)-aminosulphonyl group, for example --SO₂ N(CH₃)₂ or --SO₂ N(C₂ H₅)₂.

When any one of R¹ to R⁴ is the group --SO₂ R²¹, it is preferably a C₁₋₆ alkanesulphonyl group, a C₁₋₆ haloalkanesulphonyl group or an optionally substituted benzenesulphonyl group, for example methanesulphonyl, ethanesulphonyl, trifluoromethanesulphonyl, benzenesulphonyl or benzenesulphonyl optionally substituted with one or more substituents selected from halogen such as chlorine, fluorine or bromine, C₁₋₄ alkyl such as methyl or ethyl, C₁₋₄ alkoxy such as methoxy or ethoxy, C₁₋₄ haloalkyl such as chloromethyl, fluoromethyl, trifluoromethyl or 2,2,2-trifluoroethyl, C₁₋₄ haloalkoxy such as trifluoromethoxy or 2,2,2-trifluoroethoxy, hydroxy, cyano and nitro, for example 4-methylbenzenesulphonyl.

When any one of R¹ to R⁴ is the group --SOR²², it is preferably a C₁₋₆ alkanesulphinyl group, for example methanesulphinyl or ethanesulphinyl, or a C₁₋₆ haloalkanesulphinyl group, for example trifluoromethanesulphinyl.

When any one of R¹ to R⁴ is the group --CSNR²³ R²⁴ it is preferably --CSNH₂, --CSNHCH₃ or --CSN(CH₃)₂.

When any one of R¹ to R⁴ is the group --SiR²⁵ R²⁶ R²⁷, it is preferably a tri-(C₁₋₆ alkyl)silyl group, for example, trimethylsilyl or triethylsilyl.

When any one of R¹ to R⁴ is the group --OCH₂ CO₂ R²⁸, it is preferably a C₁₋₆ alkoxycarbonylmethoxy group, for example methoxycarbonylmethoxy or ethoxycarbonylmethoxy.

When any one of R¹ to R⁴ is the group --OCH₂ CH₂ CO₂ R²⁹, it is preferably a C₁₋₆ alkoxycarbonylethoxy group, for example methoxycarbonylethoxy or ethoxycarbonylethoxy.

When any one of R¹ to R⁴ is the group --CONR³⁰ SO₂ R³¹, it is preferably an N-(C₁₋₆ alkanesulphonyl)carboxamido group or an N-(C₁₋₆ alkyl)-N-(C₁₋₆ alkanesulphonyl)carboxamido group, for example N-(methanesulphonyl)-carboxamido or N-methyl-N-(methanesulphonyl)carboxamido.

When any one of R¹ to R⁴ is the group --NHCONR³² R³³ or --NHCSNR³² R³³, R³² and R³³ are preferably each independently a C₁₋₆ alkyl group.

When any one of R¹ to R⁴ is the group --SO₂ Z, it is preferably --SO₂ F, --SO₂ Br or SO₂ Cl.

When an adjacent pair of R¹, R², R³ and R⁴ taken together form a fused 5- or 6-membered carbocyclic or heterocyclic ring, the pair of substituents taken together is preferably --(CH₂)₃ --, --(CH₂)₄ --, --CH═CH--CH═CH--, --O--CH₂ --O-- optionally substituted with one or two halogen atoms, for example --O--CHF--O-- or --O--CF₂ --O--, --O--CH(CH₃)--O--, --O--C(CH₃)₂ --O-- or --O--(CH₂)₂ --O--, and the fused ring formed thereby is preferably a 5- or 6-membered heterocyclic ring containing two oxygen atoms and optionally substituted with one or more halogen or methyl groups, or a 5- or 6-membered carbocyclic ring.

Of particular interest are compounds of formula (I) where R¹ to R⁴ are each independently hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, SCH₃ and SCH₂ CF₃.

The nematicidal properties of compounds of formula (I) and oxidised derivatives thereof are described in UK Patent Publication No. 2270689.

Examples of the compounds of formula (I) which may be prepared according to the process of the invention are set out in Table I.

                                      TABLE I                                      __________________________________________________________________________     COMPOUND                                                                       NO.     R.sup.1      R.sup.2      R.sup.3     R.sup.4   X                      __________________________________________________________________________      1      H            H            H           H         S                       2      H            H            H           H         O                       3      H            F            H           H         O                       4      H            H            F           H         S                       5      NO.sub.2     H            H           H         O                       6      NH.sub.2     H            H           H         O                       7      CH.sub.3     H            H           H         S                       8      H            F            F           H         O                       9      H            H            H           H         O                       10     CO.sub.2 CH.sub.3                                                                           H            H           H         O                       11     NHCOCH.sub.3 H            H           H         S                       12     H            H            H           H         S                       13     COOH         H            H           H         S                       14     H            H            H           H         O                       15     F            H            H           H         S                       16     H            H            H           CH.sub.3  S                       17     H            H            CH.sub.3    H         O                       18     H            H            CH.sub.2 CH═CH.sub.2                                                                   H         O                       19     H            H            .sup.c C.sub.3 H.sub.5                                                                     H         O                       20     H            H            Cl          H         O                       21     H            H            CN          H         S                       22     H            CH.sub.3     H           H         S                       23     H            CH.sub.2 CH═CH.sub.2                                                                    H           H         O                       24     H            .sup.c C.sub.3 H.sub.5                                                                      H           H         O                       25     H            Cl           H           H         S                       26     H            C.sub.6 H.sub.5                                                                             H           H         O                       27     CH.sub.3     CH.sub.3     H           H         O                       28     Cl           Cl           H           H         S                       29     F            Cl           H           H         O                       30     OCH.sub.3    H            NHCOCH.sub.3                                                                               H         O                       31     OCH.sub.3    H            OCH.sub.3   H         O                       32     OCH.sub.3    OCH.sub.3    H           H         O                       33     1-CH.sub.3 --.sup.c C.sub.3 H.sub.5                                                         H            H           H         S                       34     OH           F            H           H         O                       35     OH           H            Cl          H         S                       36     H            H            CO.sub.2 CH.sub.3                                                                          H         O                       37     OCH.sub.2 CF.sub.3                                                                          H            H           H         S                       38     OCH.sub.2 CF.sub.3                                                                          H            H           H         O                       39     OCH.sub.2 CH.sub. 3                                                                         H            H           H         S                       40     H            H            CH.sub.2 OCH.sub.3                                                                         H         S                       41     H            CH.sub.3     H           H         O                       42     H            H            CN          H         O                       43     --CH═CH--CH═CH--  H           H         S                       44     --CH═CH--CH═CH--  H           H         O                       45     Cl           H            H           H         O                       46     Cl           H            H           H         S                       47     F            H            H           H         O                       48     CH.sub.3     H            H           H         O                       49     NHCOCH.sub.3 H            H           H         O                       50     NHCOC.sub.2 H.sub.5                                                                         H            H           H         S                       51     NHSO.sub.2 CH.sub.3                                                                         H            H           H         S                       52     NO.sub.2     H            H           H         S                       53     N(SO.sub.2 CH.sub.3).sub.2                                                                  H            H           H         O                       54     OH           H            H           H         O                       55     OCOCH.sub.3  H            H           H         O                       56     OCH.sub.2 CH.sub.3                                                                          H            H           H         S                       57     OCH.sub.3    H            H           H         O                       58     OCH.sub.3    H            H           H         S                       59     OCH.sub.3    H            H           Cl        S                       60     OSO.sub.2 CH.sub.3                                                                          H            H           H         O                       61     H            Br           H           H         S                       62     H            CF.sub.3     H           H         S                       63     H            Cl           H           H         S                       64     H            CO.sub.2 CH.sub.2 CH.sub.2 CH═CF.sub.2                                                  H           H         S                       65     H            CONH.sub.2   H           H         S                       66     H            CONHCH.sub.2 CH.sub.2 CH.sub.3                                                              H           H         S                       67     H            CON(CH.sub.3).sub.2                                                                         H           H         S                       68     H            COOH         H           H         S                       69     H            F            H           H         S                       70     H            NHCOC.sub.6 H.sub.5                                                                         H           H         S                       71     H            OCH.sub.3    H           H         S                       72     H            SCH.sub.3    H           H         S                       73     H            SO.sub.2 C.sub.2 H.sub.5                                                                    H           H         O                       74     H            SO.sub.2 CH.sub.3                                                                           H           H         S                       75     H            SO.sub.2 N(C.sub.2 H.sub.5).sub.2                                                           H           H         O                       76     H            SO.sub.2 N(CH.sub.3).sub.2                                                                  H           H         S                       77     H            H            Cl          H         S                       78     H            H            F           H         O                       79     H            H            H           CH.sub.3  O                       80     H            H            H           NH        O                       81     H            H            H           NO.sub.2  O                       82     H            H            H           OH        O                       83     H            H            H           OCH.sub.2 CH.sub.2 F                                                                     O                       84     COOH         H            H           H         O                       85     NHCHO        H            H           H         O                       86     SCH.sub.3    H            H           H         S                       87     H            Br           H           H         S                       88     H            Br           H           H         S                       89     H            Cl           H           H         O                       90     H            CN           H           H         O                       91     H            CN           H           H         S                       92     H            CO.sub.2 CH.sub.2 CH.sub.2 CH═CF.sub.2                                                  H           H         S                       93     H            CO.sub.2 CH.sub.2 CH.sub.2 CH═CF.sub.2                                                  H           H         S                       94     H            COOH         H           H         O                       95     H            F            H           H         S                       96     H            OCF.sub.3    H           H         S                       97     H            H            H           COOH      O                       98     H            H            H           NHCOC.sub.2 H.sub.5                                                                      O                       99     H            H            H           NHSO.sub.2 CH.sub.3                                                                      O                      100     H            H            H           OCOC.sub.2 H.sub.5                                                                       O                      101     H            H            H           OCH.sub.2 CH.sub.2 CH═CF                                                   .sub.2    O                      102     H            H            H           OCH.sub.3 O                      103     H            NH.sub.2     H           H         O                      104     OCH.sub.2 CCl═CH2                                                                       H            H           H         O                      105     OCH.sub.2 CH═CCl.sub.2                                                                  H            H           H         O                      106     OCH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                          H            H           H         O                      107     CN           H            H           H         O                      108     CONH.sub.2   H            H           H         O                      109     CON(CH.sub.3)C.sub.2 H.sub.5                                                                H            H           H         O                      110     OCH.sub.2 CH.sub.2 F                                                                        H            H           H         O                      111     OCH.sub.2 CH.sub.2 CH.sub.3                                                                 H            H           H         O                      112     OCH(CH.sub.3)C.sub.2 H.sub.5                                                                H            H           H         O                      113     H            SCH.sub.3    H           H         O                      114     H            H            NO.sub.2    H         O                      115     H            NO.sub.2     NO.sub.2    H         O                      116     H            CF.sub.3     H           H         O                      117     H            H            H           H         S                      118     H            CO.sub.2 CH.sub.2 CH.sub.2 CH═CF.sub.2 H                                                H           O                                119     H            H            H           NHCOCF.sub.3                                                                             O                      120     SO.sub.2 NH.sub.2                                                                           H            H           H         S                      121     H            SOCH.sub.3   H           H         S                      122     H            CONHCH.sub.3 H           H         S                      123     H            SO.sub.2 NHCH.sub.3                                                                         H           H         S                      124     H            SO.sub.2 C.sub.2 H.sub.5                                                                    H           H         S                      125     H            CSNH.sub.2   H           H         S                      126     H            NO.sub.2     H           H         S                      127     H            H            NO.sub.2    H         S                      128     --O--CH.sub.2 --O--                                                                         H            H           S                                129     SO.sub.2 F   H            H           H         S                      130     H            H            H           OCH.sub.3 S                      131     OCH.sub.3    OCH.sub.3    H           H         S                      132     H            C.tbd.CH     H           H         S                      133     H            SO.sub.2 CF.sub.3                                                                           H           H         S                      134     NHCOC.sub.6 H.sub.5                                                                         H            H           H         S                      135     H            H            H           Cl        S                      136     H            H            Br          H         S                      137     H            SCF.sub.3    H           H         S                      138     H            SOCF.sub.3   H           H         S                      139     H            COCH.sub.3   H           H         S                      140     H            SCH.sub.2 CH.sub.2 CH.sub.3                                                                 H           H         S                      141     H            I            H           H         S                      142     H            *            H           O                                ** indicates a fused --CH═CH--CH═CH-- link                             143     H            NO.sub.2     H           H         O                      144     H            H            H           CONHCH.sub.2 C.sub.6                                                           H.sub.5   O                      145     H            CONH.sub.2   H           H         O                      146     H            CO.sub.2 CH.sub.3                                                                           H           H         O                      147     OCH.sub.2 CH═CH.sub.2                                                                   H            H           H         O                      148     NH.sub.2     H            H           H         S                      149     H            OH           H           H         O                      150     H            SCF.sub.3    H           H         S                      151     H            SCF.sub.3    H           H         S                      152     H            H            H           CO.sub.2 CH.sub.3                                                                        O                      153     H            CO.sub.2 CH.sub.2CH.sub.2 F                                                                 H           H         O                      154     I            H            H           H         S                      155     C.tbd.CH     H            H           H         S                      156     H            OCH.sub.3    H           H         O                      157     H            F            H           H         S                      158     H            CONHCH.sub.2 C.sub.6 H.sub.5                                                                H           H         O                      159     OCH.sub.2 CH.sub.2 CH═CF.sub.2                                                          H            H           H         O                      160     NO.sub.2     H            H           H         S                      161     NO.sub.2     H            H           H         S                      162     --O--CH.sub.2 --O--       H           H         O                      163     --CH═CH--CH═CH--  H           H         O                      164     --CH═CH--CH═CH--  H           H         S                      165     1--CH.sub.3 .sup.c C.sub.3 H.sub.5                                                          H            H           H         O                      166     Br           H            H           H         O                      167     Br           H            H           H         S                      168     C.tbd.CH     H            H           H         O                      169     C.sub.6 H.sub.5                                                                             H            H           H         O                      170     C.sub.6 H.sub.5                                                                             H            H           H         S                      171     .sup.c C.sub.3 H.sub.5                                                                      H            H           H         O                      172     .sup.c C.sub.3 H.sub.5                                                                      H            H           H         S                      173     CF.sub.2 H.sub.2                                                                            H            H           H         O                      174     CF.sub.2 H.sub.2                                                                            H            H           H         S                      175     CF.sub.3     H            H           H         O                      176     CF.sub.3     H            H           H         S                      177     CH.sub.2 CH═CH.sub.2                                                                    H            H           H         O                      178     CH.sub.2 CH═CH.sub.2                                                                    H            H           H         S                      179     CH.sub.2 CH.sub.2 F                                                                         H            H           H         O                      180     CH.sub.2 CH.sub.2 F                                                                         H            H           H         S                      181     CH.sub.2 CH.sub.3                                                                           H            H           H         O                      182     CH.sub.2 CH.sub.3                                                                           H            H           H         S                      183     CH.sub.2 OH  H            H           H         O                      184     CH.sub.2 OH  H            H           H         S                      185     CH.sub.3     CH.sub.3     H           H         S                      186     CH.sub.3     H            H           H         O                      187     CH.sub.3     H            H           H         O                      188     CH.sub.3     H            H           H         S                      189     CH.sub.3     H            H           H         S                      190     Cl           Cl           H           H         O                      191     Cl           H            H           H         O                      192     Cl           H            H           H         S                      193     CN           H            H           H         S                      194     CO.sub.2 CH.sub.2 CH.sub.2 CH═CF.sub.2                                                  H            H           H         O                      195     CO.sub.2 CH.sub.2 CH.sub.2 CH═CF.sub.2                                                  H            H           H         O                      196     CO.sub.2 CH.sub.2 CH.sub.2 CH═CF.sub.2                                                  H            H           H         O                      197     CO.sub.2 CH.sub.2 CH.sub.2 CH═CF.sub.2                                                  H            H           H         S                      198     CO.sub.2 CH.sub.2 CH.sub.2 CH═CF.sub.2                                                  H            H           H         S                      199     CO.sub.2 CH.sub.2 CH.sub.2 CH═CF.sub.2                                                  H            H           H         S                      200     CO.sub.2 CH.sub.2 CH.sub.2 F                                                                H            H           H         O                      201     CO.sub.2 CH.sub.2 CH.sub.2 F                                                                H            H           H         S                      202     CO.sub.2 CH.sub.3                                                                           H            H           H         O                      203     CO.sub.2 CH.sub.3                                                                           H            H           H         O                      204     CO.sub.2 CH.sub.3                                                                           H            H           H         S                      205     CO.sub.2 CH.sub.3                                                                           H            H           H         S                      206     CO.sub.2 CH.sub.3                                                                           H            H           H         S                      207     COCH.sub.3   H            H           H         O                      208     COCH.sub.3   H            H           H         S                      209     CON(CH.sub.3).sub.2                                                                         H            H           H         O                      210     CON(CH.sub.3).sub.2                                                                         H            H           H         S                      211     CON(CH.sub.3)C.sub.2 H.sub.5                                                                H            H           H         S                      212     CONH.sub.2   H            H           H         S                      213     CONHCH.sub.2 C.sub.6 H.sub.5                                                                H            H           H         O                      214     CONHCH.sub.2 C.sub.6 H.sub.5                                                                H            H           H         S                      215     CONHCH.sub.2 CH.sub.2 CH═CF.sub.2                                                       H            H           H         O                      216     CONHCH.sub.2 CH.sub.2 CH═CF.sub.2                                                       H            H           H         S                      217     CONHCH.sub.2 CH.sub.2 CH.sub.3                                                              H            H           H         O                      218     CONHCH.sub.2 CH.sub.2 CH.sub.3                                                              H            H           H         S                      219     CONHCH.sub.3 H            H           H         O                      220     CONHCH.sub.3 H            H           H         S                      221     CONHSO.sub.2 CH.sub.3                                                                       H            H           H         O                      222     CONHSO.sub.2 CH.sub.3                                                                       H            H           H         S                      223     COSCH.sub.2 CH.sub.2 CH═CF.sub.2                                                        H            H           H         O                      224     COSCH.sub.2 CH.sub.2 CH═CF.sub.2                                                        H            H           H         S                      225     CSNH.sub.2   H            H           H         O                      226     CSNH.sub.2   H            H           H         S                      227     F            Cl           H           H         S                      228     I            H            H           H         O                      229     I            H            H           H         O                      230     I            H            H           H         S                      231     N(SO.sub.2 CH.sub.3).sub.2                                                                  H            H           H         S                      232     NHCHO        H            H           H         S                      233     NHCOC.sub.2 H.sub.5                                                                         H            H           H         O                      234     NHCOC.sub.6 H.sub.5                                                                         H            H           H         O                      235     NHSO.sub.2 CH.sub.3                                                                         H            H           H         O                      236     NO.sub.2     H            H           H         O                      237     NO.sub.2     H            H           H         O                      238     OCF.sub.2 CF.sub.2 H                                                                        H            H           H         O                      239     OCF.sub.2 CF.sub.2 H                                                                        H            H           H         S                      240     OCF.sub.2 H  H            H           H         O                      241     OCF.sub.2 H  H            H           H         O                      242     OCF.sub.2 H  H            H           H         O                      243     OCF.sub.2 H  H            H           H         S                      244     OCF.sub.2 H  H            H           H         S                      245     OCF.sub.2 H  H            H           H         S                      246     OCF.sub.3    H            H           H         O                      247     OCF.sub.3    H            H           H         S                      248     OCH(CH.sub.3)C.sub.2 H.sub.5                                                                H            H           H         S                      249     OCH.sub.2 CCl═CH.sub.2                                                                  H            H           H         S                      250     OCH.sub.2 CF.sub.3                                                                          H            H           H         O                      251     OCH.sub.2 CF.sub.3                                                                          H            H           H         S                      252     OCH.sub.2 CH═CCl.sub.2                                                                  H            H           H         S                      253     OCH.sub.2 CH═CH.sub.2                                                                   H            H           H         S                      254     OCH.sub.2 CH.sub.2 CH═CF.sub.2                                                          H            H           H         S                      255     OCH.sub.2 CH.sub.2 CH.sub.3                                                                 H            H           H         S                      256     OCH.sub.2 CH.sub.2 F                                                                        H            H           H         S                      257     OCH.sub.2 CH.sub.3                                                                          H            H           H         O                      258     OCH.sub.2 CH.sub.3                                                                          H            H           H         O                      259     OCH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                          H            H           H         S                      260     OCH.sub.3    H            H           Cl        O                      261     OCH.sub.3    H            NHCOCH.sub.3                                                                               H         S                      262     OCH.sub.3    H            OCH.sub.3   H         S                      263     OCOCH.sub.3  H            H           H         S                      264     OH           F            H           H         S                      265     OH           H            Cl          H         O                      266     OH           H            H           H         S                      267     OSO.sub.2 CH.sub.3                                                                          H            H           H         S                      268     SCF.sub.3    H            H           H         O                      269     SCF.sub.3    H            H           H         S                      270     SCH.sub.2 CH.sub.2 CH.sub.3                                                                 H            H           H         O                      271     SCH.sub.2 CH.sub.2 CH.sub.3                                                                 H            H           H         S                      272     SCH.sub.3    H            H           H         O                      273     SO.sub.2 C.sub.2 H.sub.5                                                                    H            H           H         O                      274     SO.sub.2 C.sub.2 H.sub.5                                                                    H            H           H         S                      275     SO.sub.2 CF.sub.3                                                                           H            H           H         O                      276     SO.sub.2 CF.sub.3                                                                           H            H           H         S                      277     SO.sub.2 CH.sub.3                                                                           H            H           H         O                      278     SO.sub.2 CH.sub.3                                                                           H            H           H         S                      279     SO.sub.2 F   H            H           H         O                      280     SO.sub.2 N(C.sub.2 H.sub.5).sub.2                                                           H            H           H         O                      281     SO.sub.2 N(C.sub.2 H.sub.5).sub.2                                                           H            H           H         S                      282     SO.sub.2 N(CH.sub.3).sub.2                                                                  H            H           H         O                      283     SO.sub.2 N(CH.sub.3).sub.2                                                                  H            H           H         S                      284     SO.sub.2 NH.sub.2                                                                           H            H           H         O                      285     SO.sub.2 NHCH.sub.3                                                                         H            H           H         O                      286     SO.sub.2 NHCH.sub.3                                                                         H            H           H         S                      287     SOCF.sub.3   H            H           H         O                      288     SOCF.sub.3   H            H           H         S                      289     SOCH.sub.3   H            H           H         O                      290     SOCH.sub.3   H            H           H         S                      291     H            H            S                                            ** indicates a fused --CH═CH--CH═CH-- link                             292     H            1--CH.sub.3 --.sup.c C.sub.3 H.sub.5                                                        H           H         O                      293     H            1--CH.sub.3 --.sup.c C.sub.3 H.sub.5                                                        H           H                                294     H            Br           H           H         O                      295     H            Br           H           H         O                      296     H            Br           H           H         O                      297     H            C.tbd.CH     H           H         O                      298     H            C.sub.6 H.sub.5                                                                             H           H         S                      299     H            .sup.c C.sub.3 H.sub.5                                                                      H           H         S                      300     H            CF.sub.2 H.sub.2                                                                            H           H         O                      301     H            CF.sub.2 H.sub.2                                                                            H           H         S                      302     H            CH.sub.2 CH═CH.sub.2                                                                    H           H         S                      303     H            CH.sub.2 CH.sub.2 F                                                                         H           H         O                      304     H            CH.sub.2 CH.sub.2 F                                                                         H           H         S                      305     H            CH.sub.2 CH.sub.3                                                                           H           H         O                      306     H            CH.sub.2 CH.sub.3                                                                           H           H         S                      307     H            CH.sub.2 OH  H           H         O                      308     H            CH.sub.2 OH  H           H         S                      309     H            CHO          H           H         O                      310     H            CHO          H           H         S                      311     H            Cl           H           H         O                      312     H            CO.sub.2 CH.sub.2 CH.sub.2 CH═CF.sub.2 H                                                H           O                                313     H            CO.sub.2 CH.sub.2 CH.sub.2 CH═CF.sub.2 H                                                H           O                                314     H            CO.sub.2 CH.sub.2 CH.sub.2 F                                                                H           H         S                      315     H            CO.sub.2 CH.sub.2 CH.sub.3                                                                  H           H         O                      316     H            CO.sub.2 CH.sub.2 CH.sub.3                                                                  H           H         S                      317     H            CO.sub.2 CH.sub.3                                                                           H           H         S                      318     H            COCH.sub.3   H           H         O                      319     H            CON(CH.sub.3).sub.2                                                                         H           H         O                      320     H            CON(CH.sub.3)C.sub.2 H.sub.5                                                                H           H         O                      321     H            CON(CH.sub.3)C.sub.2 H.sub.5                                                                H           H         S                      322     H            CONHCH.sub.2 C.sub.6 H.sub.5                                                                H           H         S                      323     H            CONHCH.sub.2 CH.sub.2 CH═CF.sub.2                                                       H           H         O                      324     H            CONHCH.sub.2 CH.sub.2 CH═CF.sub.2                                                       H           H         S                      325     H            CONHCH.sub.2 CH.sub.2 CH.sub.3                                                              H           H         O                      326     H            CONHCH.sub.3 H           H         O                      327     H            CONHSO.sub.2 CH.sub.3                                                                       H           H         O                      328     H            CONHSO.sub.2 CH.sub.3                                                                       H           H         S                      329     H            COSCH.sub.2 CH.sub.2 CH═CF.sub.2                                                        H           H         O                      330     H            COSCH.sub.2 CH.sub.2 CH═CF.sub.2                                                        H           H         S                      331     H            CSNH.sub.2   H           H         O                      332     H            F            H           H         O                      333     H            F            H           H         O                      334     H            F            F           H         S                      335     H            I            H           H         O                      336     H            N(SO.sub.2 CH.sub.3).sub.2                                                                  H           H         O                      337     H            N(SO.sub.2 CH.sub.3 ).sub.2                                                                 H           H         S                      338     H            NH.sub.2     H           H         S                      339     H            NHCHO        H           H         O                      340     H            NHCHO        H           H         S                      341     H            NHCOC.sub.2 H.sub.5                                                                         H           H         O                      342     H            NHCOC.sub.2 H.sub.5                                                                         H           H         S                      343     H            NHCOC.sub.6 H.sub.5                                                                         H           H         O                      344     H            NHCOCH.sub.3 H           H         O                      345     H            NHCOCH.sub.3 H           H         S                      346     H            NHSO.sub.2 CH.sub.3                                                                         H           H         O                      347     H            NHSO.sub.2 CH.sub.3                                                                         H           H         S                      348     H            NO.sub.2     H           H         O                      349     H            NO.sub.2     NO.sub.2    H         S                      350     H            OCF.sub.2 CF.sub.2 H                                                                        H           H         O                      351     H            OCF.sub.2 CF.sub.2 H                                                                        H           H         S                      352     H            OCF.sub.2 H  H           H         O                      353     H            OCF.sub.2 H  H           H         O                      354     H            OCF.sub.2 H  H           H         O                      355     H            OCF.sub.2 H  H           H         S                      356     H            OCF.sub.2 H  H           H         S                      357     H            OCF.sub.2 H  H           H         S                      358     H            OCF.sub.3    H           H         O                      359     H            OCH(CH.sub.3)C.sub. 2 H.sub.5                                                               H           H         O                      360     H            OCH(CH.sub.3)C.sub.2 H.sub.5                                                                H           H         S                      361     H            OCH.sub.2 CCl═CH.sub.2                                                                  H           H         O                      362     H            OCH.sub.2 CCl═CH.sub.2                                                                  H           H         S                      363     H            OCH.sub.2 CF.sub.3                                                                          H           H         O                      364     H            OCH.sub.2 CF.sub.3                                                                          H           H         S                      365     H            OCH.sub.2 CH═CCl.sub.2                                                                  H           H         O                      366     H            OCH.sub.2 CH═CCl.sub.2                                                                  H           H         S                      367     H            OCH.sub.2 CH═CH.sub.2                                                                   H           H         O                      368     H            OCH.sub.2 CH═CH.sub.2                                                                   H           H         S                      369     H            OCH.sub.2 CH.sub.2 CH═CF.sub.2                                                          H           H         O                      370     H            OCH.sub.2 CH.sub.2 CH═CF.sub.2                                                          H           H         S                      371     H            OCH.sub.2 CH.sub.2 CH.sub.3                                                                 H           H         O                      372     H            OCH.sub.2 CH.sub.2 CH.sub.3                                                                 H           H         S                      373     H            OCH.sub.2 CH.sub.2 F                                                                        H           H         O                      374     H            OCH.sub.2 CH.sub.2 F                                                                        H           H         S                      375     H            OCH.sub.2 CH.sub.3                                                                          H           H         O                      376     H            OCH.sub.2 CH.sub.3                                                                          H           H         O                      377     H            OCH.sub. 2 CH.sub.3                                                                         H           H         S                      378     H            OCH.sub.2 CH.sub.3                                                                          H           H         S                      379     H            OCH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                          H           H         O                      380     H            OCH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                          H           H         S                      381     H            OCH.sub.3    H           H         O                      382     H            OCH.sub.3    H           H         O                      383     H            OCH.sub.3    H           H         S                      384     H            OCH.sub.3    H           H         S                      385     H            OCOCH.sub.3  H           H         O                      386     H            OCOCH.sub.3  H           H         S                      387     H            OH           H           H         S                      388     H            OSO.sub.2 CH.sub.3                                                                          H           H         O                      389     H            OSO.sub.2 CH.sub.3                                                                          H           H         S                      390     H            SCF.sub.3    H           H         O                      391     H            SCF.sub.3    H           H         O                      392     H            SCF.sub.3    H           H         O                      393     H            SCH.sub.2 CH.sub.2 CH.sub.3                                                                 H           H         O                      394     H            SO.sub.2 CF.sub.3                                                                           H           H         O                      395     H            SO.sub.2 CH.sub.3                                                                           H           H         O                      396     H            SO.sub.2 F   H           H         O                      397     H            SO.sub.2 F   H           H         S                      398     H            SO.sub.2 N(C.sub.2 H.sub.5).sub.2                                                           H           H         S                      399     H            SO.sub.2 N(CH.sub.3).sub.2                                                                  H           H         O                      400     H            SO.sub.2 NH.sub.2                                                                           H           H         O                      401     H            SO.sub.2 NH.sub.2                                                                           H           H         S                      402     H            SO.sub.2 NHCH.sub.3                                                                         H           H         O                      403     H            SOCF.sub.3   H           H         O                      404     H            SOCH.sub.3   H           H         O                      405     H            H            H           Cl        O                      406     H            H            H           CO.sub.2 CH.sub.3                                                                        S                      407     H            H            H           CONHCH.sub.2 C.sub.6                                                           H.sub.5   S                      408     H            H            H           COOH      S                      409     H            H            H           NH.sub.2  S                      410     H            H            H           NHCOC.sub.2 H.sub.5                                                                      S                      411     H            H            H           NHCOCF.sub.3                                                                             S                      412     H            H            H           NHSO.sub.2 CH.sub.3                                                                      S                      413     H            H            H           NO.sub.2  S                      414     H            H            H           OCH.sub.2 CH.sub.2 CH═CF                                                   .sub.2    S                      415     H            H            H           OCH.sub.2 CH.sub.2 F                                                                     S                      416     H            H            H           OCOC.sub.2 H.sub.5                                                                       S                      417     H            H            H           OH        S                      418     H            H            Br          H         O                      419     H            H            CH.sub.2 OCH.sub.3                                                                         H         O                      420     H            H            COOH        H         O                      421     H            H            OCH.sub.3   H         O                      422     H            H            OH          H         O                      423     H            H            CN          H         O                      424     H            H            OCH.sub.3   H         O                      425     H            H            F           H         O                      426     H            H            OCH.sub.3   H         O                      427     H            H            cc H        H         S                      428     H            H            CH.sub.2 CH═CH.sub.2                                                                   H         S                      429     H            H            CH.sub.3    H         S                      430     H            H            CO.sub.2 CH.sub.3                                                                          H         S                      431     H            H            COOH        H         S                      432     H            H            F           H         S                      433     H            H            OCH         H         S                      434     H            H            OH          H         S                      435     H            H            CN          H         S                      436     H            H            OCH.sub.3   H         S                      437     H            H            H           H         S                      438     H            H            OCH.sub.3   H         S                      439     CH═CH    H            H           H         S                      440     CH═CH.sub.2                                                                             H            H           H         O                      441     H            CH═CH.sub.2                                                                             H           H         O                      442     H            CH═CH.sub.2                                                                             H           H         S                      __________________________________________________________________________      .sup.c indicates a cyclic substituent.                                   

The process of step (a) of the invention described above has not previously been reported. Accordingly, in another aspect, the invention provides a process of making an optionally substituted 2-mercaptobenz-oxazole or -thiazole having the formula (III) wherein R¹ -R⁴ are as hereinbefore defined, which comprises reacting an optionally substituted ortho-nitro or -nitroso phenol or ortho-nitro or -nitroso thiophenol of formula (II) wherein R¹ -R⁴ are as hereinbefore defined, y is 1 or 2, and X is oxygen or sulphur, with a reducing agent comprising an alkali metal dithionite in an alkaline reaction medium in the presence of carbon disulphide to form the optionally substituted 2-mercaptobenz-oxazole or -thiazole of formula (III), acidifying the reaction medium, and collecting the 2-mercaptobenz-oxazole or -thiazole.

Compounds of formula (IV) wherein L is OSO2R^(a) may be prepared by the following sequence of reactions. Hydrogen bromide is reacted with the commercially available compound of Formula (V) under standard conditions for an addition reaction, for example by passing hydrogen bromide gas through a solution of the compound of Formula (V) in an inert solvent, optionally in the presence of a free-radical generator (e.g. benzoyl peroxide) to give the compound of formula (VI). The compound of formula (VI) is then reacted with the silver salt of a sulphonic acid of formula R^(a) SO₃ H, wherein R^(a) has the meaning given above, for example the silver salt of 4-methylbenzenesulphonic acid (silver tosylate) or the silver salt of methanesulphonic acid (silver mesylate), preferably in an inert solvent in the absence of light, to give the corresponding compound of Formula (VII). Debromofluorination of the compound of formula (VII), for example by reaction with zinc, preferably in the presence of a suitable catalyst such as iodine, gives the compound (III), wherein R^(a) has the meanings given above.

The compound of formula (IV) wherein L is bromine, i.e. 4-bromo-1,1-difluorobut-1-ene may be prepared by the following sequence of reactions: Hydrogen bromide is reacted with the commercially available compound 4-bromo-1,1,2-trifluorobut-1-ene having the formula (V), under standard conditions for an addition reaction, for example by passing hydrogen bromide gas through a solution of 4-bromo-1,1,2-trifluorobut-1-ene in an inert solvent, optionally in the presence of a free radical generator (e.g. benzoyl peroxide), to give 1,4-dibromo-1,1,2-trifluorobutane (Formula (VI). This compound is then treated with a debromofluorinating agent, which removes a bromine atom and a fluorine atom from the 1,4-dibromo-1,1,2-trifluorobutane to give 4-bromo-1,1-difluorobut-1-ene (IV, L=Br). Examples of debromofluorinating agents include zinc, magnesium and aluminium.

Compounds of formula (IV) wherein L is another halogen atom may be prepared in a similar way to that described above wherein L is bromine.

Various preferred features and embodiments of the present invention will now be described by way of non-limiting example with reference to the following Examples.

Examples 1 to 4 illustrate step (a) of the process of the present invention.

EXAMPLE 1 Preparation of 6-methoxy-2-mercaptobenzoxazole

Carbon disulphide (9 ml, 0.15 mol) was added dropwise over a period of 1 minute to a solution of potassium hydroxide (6.5 g, 0.12 mol) in a mixture of water (10 ml) and methanol (100 ml), followed by 2-nitro-5-methoxyphenol (16.9 g, 0.1 mol). ]The 2-nitro-5-methoxyphenol required as starting material was prepared by nitration of 3-methoxyphenol as described in Synthetic Communications, 1993, 23(3) 343-348.] To this mixture was added dropwise a solution of potassium hydroxide (39 g, 0.7 mol) and sodium dithionite (65 g, 0.3 mol), over a period of 15 minutes, so that the temperature did not exceed 40° C. The reaction mixture was then cooled to room temperature and carbon disulphide (0.9 ml, 0.15 mol) added and the resulting solution heated to 80° C. for 2 hours. The mixture was then cooled and acidified with concentrated hydrochloric acid to a pH of 3. The pale yellow precipitate was collected and air dried to yield 6-methoxy-2-mercaptobenzoxazole (16.6 g, 89%).

Proton NMR (CDCl₃): δ 2.85(3H, OCH₃); 6.9(1H, dd, aromatic C--H); 6.95(1H, d, aromatic C--H); 7.13(H, d, aromatic C--H); 11.0 (H, bs, SH).

Following the above procedure, 6-methoxy-2-mercaptobenzthiazole may be prepared in a similar way, using 2-nitro thiophenol as starting material.

EXAMPLE 2 Preparation of 6-hydroxy-2-mercaptobenzoxazole

Carbon disulphide (0.9 ml, 15 mmol) was added to a solution of potassium hydroxide (0.65 g, 11 mmol) in a mixture of water (1 ml) and methanol (10 ml), followed by 4-nitro 1,2-benzenediol (1.5 g, 10 mmol). To this mixture was added dropwise a solution of sodium dithionite (6,5 g, 30 mmol) and potassium hydroxide (3.9 g, 70 mmol) in water (50 ml); strong heat evolution was observed. After 10 minutes, carbon disulphide (0.9 ml, 15 mmol) was added and the mixture heated to 75° C. for 3 hours. The mixture was then cooled in an ice bath and the precipitate filtered off. The filtrate was acidified to approximately pH3 with concentrated hydrochloric acid and the yellow precipitate was collected, washed with water and air dried. The yield was 1.05 g (65%).

Proton NMR (CDCl₃): δ 3.30(1H, bs, OH); 7.68(1H, dd, aromatic C--H); 6.84(1H, d, aromatic C--H); 7.00(1H, d, aromatic C--H) and 9.75 (1H, bs, SH).

EXAMPLE 3 Preparation of 5-methoxy-2-mercaptobenzoxazole

Carbon disulphide (886 mg, 0.7 ml, 11.6 mmol) was added dropwise to KOH (800 mg, 14.3 mmol) dissolved in methanol (8 ml) and water (15 ml), and the resulting yellow solution stirred for 4 minutes at room temperature. This was added to a mixture of 3-methoxy-6-nitrophenol (1.2 g, 7.1 mmol), KOH (2.0 g, 35.7 mmol) and water (35 ml), followed by the addition of first solid sodium dithionite (3.7 g, 21.2 mmol), then carbon disulphide (760 mg, 9.9 mmol). The resulting mixture was stirred at 70° C. for 20 hours.

The reaction mixture was cooled to room temperature, acidified with concentrated HCl and the resulting precipitated solid collected by filtration and air dried. The yield was 980 mg (76%).

Proton NMR (CDCl₃ /D₆ -DMSO): δ 3.80 (3H, s, OCH₃), 6.75 (2H, m, aromatic C--H), 7.50 (1H, d, aromatic C--H), and 13.20 (1H, bs, SH).

EXAMPLE 4 Preparation of 5-trifluoromethyl-2-mercaptobenzthiazole

Carbon disulphide (2.28 g, 30 mmol) was added dropwise over a period of 1 minute to a solution of potassium hydroxide (0.33 g, 5.9 mmol) in a mixture of water (2 ml) and methanol (5 ml), and the resulting yellow solution stirred for 5 minutes, followed by the addition of 2-nitro-4-trifluoromethyl thiophenol (1.10 g, 5 mmol). To this mixture was added dropwise over a period of 5 minutes a solution of potassium hydroxide (1.97 g, 35 mmol) and sodium dithionite (3.1 g, 15 mmol) in water (14 ml), so that the temperature did not exceed 40° C. The resultant orange mixture was stirred at 40°-50° C. for 2 hours. The reaction mixture was cooled to 10° C. and slowly acidified to pH 5-6 with concentrated HCl, and the mixture stirred for half an hour at this temperature. The off-white solid was washed with water and air dried to give the product. The yield was 0.81 g (70%).

Proton NMR (CDCl₃): δ 7.45 (1H, d, aromatic C--H), 7.50 (1H, d, aromatic C--H), 7.55 (1H, s, aromatic C--H) and 13.50 (1H, bs, SH);

mass spectrum (EI/CI) 251 (M⁺ +NH⁺ ₄), 236 (MH⁺).

Examples 5 and 6 illustrate step (b) of the process of the present invention.

EXAMPLE 5 Preparation of 2-(4,4-difluorobut-3-enyl) thiobenzoxazole (Compound No. 2)

2-Mercaptobenzoxazole (4.79 g) was added to a solution of 1,1-difluorobut-1-en-4-yl 4-methylbenzenesulphonate (6.4 g) in acetone (200 cm³) containing potassium carbonate (5.06 g). The mixture was heated to reflux overnight (17 hr) and gc used to confirm that the 1,1-difluorobut-1-en-4-yl 4-methylbenzenesulphonate had been consumed and the product had formed. The reaction mass was allowed to cool and was filtered through a plug of High-Flo filter aid to remove insoluble inorganic material. The solid material was washed with ethyl acetate and the combined organic portions evaporated under reduced pressure to give 7.1 g of a brown oily residue. This material was fractionated by eluting through a bed of silica using hexane/ethyl acetate (40:1 by volume) as solvent to give the required product as a colourless oil (5.4 g, 92% based on the sulphonate); M⁺ =241;

Proton NMR (CDCl₃): δ 2.5-2.6 (m, 2H), 3.3-3.4 (t, 2H), 4.2-4.4 (m, 1H), 7.2-7.35 (m, 2H), 7.45 (dd, 1H), 7.6 (dd, 1H).

EXAMPLE 6 Preparation of 2-(4,4-difluorobut-3-enyl) thio-4-nitrobenzoxazole (Compound No. 81)

To a brown stirred suspension of 2-mercapto-4-nitrobenzoxazole (Example 2C, 550 mg) and potassium carbonate (375 mg) in acetone (15 cm³) was added 4,4-difluorobut-3-enyl p-tolylsulphonate (700 mg) and the mixture was heated under reflux for 21 hours. The reaction was quenched by the addition of water, and extracted three times with ethyl acetate. The combined organic layers were washed with water, brine and dried (MgSO₄). Filtration and evaporation under reduced pressure gave a brown solid (806 mg). Recrystallisation from ethyl acetate and hexane gave 2-[4,4-difluorobut-3-enylthio]-4-nitrobenzoxazole as a brown crystalline solid (396 mg). GC analysis indicated that the material was >99% pure.

Proton NMR (CDCl₃) δ: 8.14(1H,d); 7.75(1H,d); 7.39(1H,t); 4.34(1H,m); 3.48(2H,t); 2.61(2H,m).

It will be appreciated that Examples 5 and 6 illustrate a general procedure for the preparation of 2-(4,4-difluorobut-3-enyl) thio-substituted benzoxazoles and benzthiazoles, and that the intermediates prepared in Examples 1 to 4 can be reacted in an analogous fashion to prepare the corresponding final product. Similarly the benzoxazole compounds used in Examples 5 and 6 can be prepared in accordance with the procedure illustrated in Examples 1 to 4. ##STR2## 

We claim:
 1. A process for the preparation of a compound of formula (I)wherein R¹, R², R³, and R⁴ are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted arylalkoxy, alkoxy, alkenyloxy, alkynyloxy, hydroxyalkyl, alkoxyalkyl, alkylthio, alkenylthio, alkynylthio, haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, haloalkenyloxy, haloalkynyloxy, haloalkylthio, haloalkenylthio, haloalkynylthio, halogen, hydroxy, cyano, nitro, --NR⁵ R⁶, --NR⁷ COR⁸, --NR⁷ CSR⁸, --NR⁹ SO₂ R¹⁰, --N(SO₂ --R¹¹), --(SO₂ --R¹²), --COR¹³, --CONR¹⁴ R¹⁵, --COOR¹⁶, --OCOR¹⁷, --OSO₂ R¹⁸, --SO₂ NR¹⁹ R²⁰, --SO₂ R²¹, --SOR²², --CSNR²³ R²⁴, --SiR²⁵ R²⁶ R²⁷, --OCH₂ CO₂ R²⁸, --OCH₂ CH₂ CO₂ R²⁹, --SO₂ Z, --CONR³⁰ SO₂ R³¹, --NHCONR³² R³³, --NHCSNR³² R³³ or an adjacent pair of R¹, R², R³ and R⁴ when taken together form a fused 5- or 6-membered carbocyclic or heterocyclic ring; R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³² and R³³ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl and optionally substituted arylalkyl; Z is halogen; and X is oxygen or sulphur, which comprises (a) reacting a substituted ortho-nitro or -nitroso phenol or a substituted ortho-nitro or -nitroso thiophenol of formula (II), ##STR3## wherein R¹ -R⁴ and X have the values previously defined, and y is 1 or 2, with a reducing agent comprising an alkali metal dithionite in an alkaline reaction medium in the presence of carbon disulphide, to form the substituted 2-mercaptobenz-oxazole or -thiazole of formula (III) ##STR4## wherein R¹ -R⁴ and X have the values previously defined, acidifying the reaction mixture and collecting the 2-mercaptobenz-oxazole or -thiazole; and (b) reacting the 2-mercaptobenz-oxazole or -thiazole (III), with a compound of formula (IV)

    CF.sub.2 ═CH--CH.sub.2 --CH.sub.2 --L                  (IV)

wherein L is a good leaving group to form the compound of formula (I).
 2. A process according to claim 1, in which L is a halogen atom, or an OSO₂ R^(a) group wherein R^(a) is a C₁₋₄ alkyl group, or a phenyl group optionally substituted with a C₁₋₄ alkyl group.
 3. A process according to claim 1, in which the reaction of the compound of formula (III) with a compound of formula (IV) is carried out at a temperature in the range of about 40°-100° C.
 4. A process according to claim 1, in which the alkali metal dithionite reducing agent is sodium dithionite.
 5. A process according to claim 1, in which the alkaline reaction medium is an aqueous alcoholic solution of an alkali metal hydroxide.
 6. A process according to claim 1, in which the alkaline reaction medium is a solution of sodium or potassium hydroxide in methanol or ethanol containing water.
 7. A process according to claim 1, in which a compound of formula (II) is reacted to form a compound of formula (III) at a temperature of from room temperature to about 80° C. 